ABSTRACT Cannabis use disorder (CUD) is a well-recognized syndrome characterized by tolerance and withdrawal. Repeated cannabis exposure is associated with downregulation and desensitization of the brain endocannabinoid (eCB) system. While several medications have been tested for CUD, none are U/S Food and Drug Administration (FDA) approved or clinically accepted. Substitution treatment while showing some promise in reducing the cannabis withdrawal syndrome (CWS), is limited by its psychoactive effects, abuse liability, and by its limited relapse prevention effects. In individuals with CUD, in vivo imaging studies have demonstrated: 1) lower brain cannabinoid receptors (CB1R) and 2) lower levels of the eCB-metabolizing enzyme fatty acid amide hydrolase (FAAH) which is responsible for degrading anandamide (AEA), a principal endogenous ligand of the cannabinoid system. Thus, an alternative to substitution treatment may be to potentiate signaling through the eCB system to restore eCB tone that is altered with chronic cannabis exposure. FAAH inhibitors which increase AEA levels reduce CWS in THC-dependent animals. PF-04457845 is an orally active, long- acting, potent, and selective FAAH inhibitor. In our completed proof of concept (POC), double-blind, randomized, placebo-controlled, inpatient/outpatient study relative to placebo, the FAAH inhibitor PF-04457845 (4mg QD) administered for 4 weeks reduced 1) cannabis withdrawal, 2) cannabis use, and 3) disturbances in sleep, in DSM-4 cannabis dependent individuals (n=60). PF-04457845 was very well-tolerated and was not rewarding/reinforcing. Hypotheses: PF-04457845 will reduce cannabis use, withdrawal symptoms, and sleep disturbances including time in Stage N3 sleep, in treatment-seeking individuals with a cannabis use disorder (CUD). Approach: The efficacy and safety of PF-04457845 (4 mg QD) on cannabis use will be studied in treatment- seeking male and female CUD subjects (n= 260 [including 25% attrition]) in a placebo-controlled, double-blind, randomized, multicenter, 12-week long (8 weeks of treatment & 4 weeks follow up) parallel-group study. Innovation: The proposed treatment for CUD is based on a plausible and novel mechanism (i.e., FAAH inhibition) that will restore eCB tone, thereby reducing cannabis use and the withdrawal syndrome. There are very few FAAH-inhibitors that are available or approved for use in humans, and none are available commercially. The proposed study builds on the promising findings of a completed POC study with the same drug at the same dose.